Peripheral blood and granuloma CD4(+)CD28(-) T cells are a major source of interferon-gamma and tumor necrosis factor-alpha in Wegener's granulomatosis

Am J Pathol. 2002 May;160(5):1717-24. doi: 10.1016/s0002-9440(10)61118-2.


To elucidate whether the fraction of CD28(-) T cells within the CD4(+) T-cell population is a major source of Th1-like and proinflammatory cytokine production driving Wegener's granulomatosis (WG) granuloma formation, we analyzed the phenotype and functional characteristics of peripheral blood CD4(+)CD28(-) T cells and of T cells in granulomatous lesions of 12 patients with active WG. Surface markers and intracytoplasmic cytokine and perforin expression were assessed by flow cytometry. Cytokine secretion was measured by enzyme-linked immunosorbent assay. Immunohistological studies demonstrated interferon-gamma and tumor necrosis factor-alpha cytokine positivity attributable to CD4(+)CD28(-) T cells in granulomatous lesions. Peripheral blood CD4(+)CD28(-) T cells expressed CD57, also found on natural killer cells, and intracytoplasmic perforin. They were generally CD25 (interleukin-2 receptor)-negative. CD18 (adhesion molecule beta(2)-integrin) was strongly up-regulated on CD4(+)CD28(-) T cells, whereas only a minority of CD4(+)CD28(+) T cells expressed CD18. CD4(+)CD28(-) T cells appeared as a major source of interferon-gamma and tumor necrosis factor-alpha. In contrast, CD4(+)CD28(+) T cells were able to produce and secrete a wider variety of cytokines including interleukin-2. One-quarter of CD4(+)CD28(+) T cells expressed the activation marker CD25, but they lacked perforin. Thus, CD4(+)CD28(-) T cells appeared more differentiated than CD4(+)CD28(+) T cells. They displayed Th1-like cytokine production and features suggestive of the capability of CD4(+) T-cell-mediated cytotoxicity. CD4(+)CD28(-) T cells may be recruited into granulomatous lesions from the blood via CD18 interaction, and may subsequently promote monocyte accumulation and granuloma formation through their cytokine secretion in WG.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CD28 Antigens / analysis
  • CD4 Antigens / analysis
  • Cytokines / biosynthesis
  • Cytokines / metabolism
  • Cytoplasm / metabolism
  • Female
  • Flow Cytometry
  • Granuloma / pathology*
  • Granulomatosis with Polyangiitis / metabolism
  • Granulomatosis with Polyangiitis / pathology*
  • Humans
  • Immunohistochemistry
  • Interferon-gamma / metabolism*
  • Lymphocyte Subsets / immunology
  • Lymphocyte Subsets / metabolism
  • Male
  • Middle Aged
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism*
  • Tumor Necrosis Factor-alpha / metabolism*


  • CD28 Antigens
  • CD4 Antigens
  • Cytokines
  • Tumor Necrosis Factor-alpha
  • Interferon-gamma